Storage stable surgically absorbable polyglycolic acid products

ABSTRACT

A dry absorbable synthetic surgical element of a polymer subject to hydrolytic degradation to non-toxic, tissue-compatible, absorbable components, such as a polyglycolic acid suture, is package in an air-tight sealed container which is substantially impervious to water vapor such as a laminate film having a metallic foil layer. The gaseous contents of the envelope are, prior to sealing the suture within the envelope, either evacuated or replaced with a gas which is inert towards said surgical element and which is substantially free from water. The water content should be below 0.5 percent by weight of the weight of the surgical element, and preferably is below 0.05 percent by weight. Polyglycolic acid sutures and other elements thus packaged retain acceptable levels of strength for at least one year at storage temperatures of 72*F. and ambient humidity outside the package. The contents may be sterilized by using ethylene oxide.

451 Apr. 24,3973

1 1 STORAGE STABLE SURGICALLY ABSORBABLE POLYGLYCOLIC ACID PRODUCTS [75]Inventor: Arthur Glick, Danbury, Conn.

[73] Assignee: American Cyanamid Stamford, Conn.

22 Filed: Apr.29,l 97l [21] Appl.No.: 138,425

Company,

Related US. Application Data [63] Continuation-impart of Ser. No.788,501, Jan. 2, I

1969, abandoned.

UNITED STATES PATENTS 3,043,067 7/1962 Rynkiewicz et al ..53/2l FC X ETH Y1. ENE

OXIDE S TEE/L IZA 770/1! 3,613,879 10/1971 Kremble ..206/63.3

Primary ExaminerTravis S. McGehee Atz0mey-Samuel Branch Walker 5 7ABSTRACT A dry absorbable synthetic surgical element of a polymersubject to hydrolytic degradation to non-toxic, tissue-compatible,absorbable components, such as a polyglycolic acid suture, is package inan air-tight sealed container which is substantially impervious to watervapor such as a laminate film having a metallic foil layer. The gaseouscontents of the envelope are, prior to scaling the suture within theenvelope, either evacuated or replaced with a gas which is inert towardssaid surgical element and which is substantially free from water. Thewater content should be below 0.5 percent by weight of the weight of thesurgical element, and preferably is below 0.05 percent by weight.Polyglycolic acid sutures and other elements thus packaged retainacceptable levels of strength for at least one year at storagetemperatures of 72F. and

6 Claims, 10 Drawing Figures ETHYL E/vE OX/DE STER/L/ZA r/0/v VACUUM 0F.SUTURE A/VD DRY ENVELOPE DRYAREA STER/LE AREA 22 r p r r p 1 1 l I 1 1I 1 l L. a u

a/isEbl/s cour E/vrs 0F ENVELOPE ARE EVACUA rEp AND THE ENVELOPE sEALEz;

Patented April 24, 1973 5 Sheets-Sheet 1 AL UMl/VUM FO/L LOW DENSITY{01. YETHYLE/VE RAE/(AGE EXTERIOR PACKAGE UVTER/UR OONTA/lVl/VG' THE.S'U TURE /5 -POL YETH YLE/VE/ LOW DENSITY BLEAOHED POUCH PAPER (V/RGl/VSULPHATE PULP) PAC/(AGE EXTERIOR XNVENTOR. ARTHUR GL/CK ATTORNEYPatented April 24, 1973 5 Sheets-Sheet VACUUM DRY ETHYLE/VE OX/DE OF.SUTUREA/VO ENVELOPE PRODUCT INVENTOR. ARTHUR GL/CK WWW ATTORNEYPatented April 24, 1973 5 Sheets-Sheet 5 E L w W a m .m R W W M H 17 N mm M N0 u n n H AR N YWN M E LU m I6 R m w WE MM M F M R) R R L P A w MmWW m 3 MA .Ar M 6M A M /K T E A R 0 E R 0 6 G 0 M 2 T T A N mm .TM a D O05 m A0 M E T T T 0 4 v! E0 DMD 5 R0 0 R A K NPP R 8 3 m 00 E TDT TN E5H A w wm 0 A 1 CNN 2 5 m #wm ESP h h 0 0 0 0 U 0 0 O 0 9 a 7 w 5 4 3(AFTER PACKAGING) EFFECT OF CONDITIONS UNDER WHICH A DR) 3-0 SUTURE ISSTORED PRIOR TO PACKAGING UPON I5 DAY IN-V/VO STRAIGHT PULL STRENGTHRETENTION DR) STORAGE AT ROOM TEMPERATURE (DESICCATOR) STORAGE ATRELATIVE HUMIDITY AND ROOM TEMPERATURE STORAGE AT RELATIVE HUMIDITY ANDROOM TEMPERATURE INVENTOR. ARTHUR GL/CK -4 5 WEEKS STORED AT 52 h O 0 O0 0 7 6 5 4 3 (AFTER PACKAGING} A TTOR/VE) Patented April 24, 1973 5Sheets-Sheet 4 J T T 5 MM m KAI. AWAL D L mmw mu P5P MWSP 1 7 7/ m U m um 6 HA v IO U W: 6 u w Q o 3 3 S S C D I I 2 DAYS STORED AT /OO"F AND/OO% Rh. (AFTER PACKAGING) DAYS STORED AT /32F AND /O% R./'/.

M 0m Am Wm K A L M V A L mm mm M50, MWSP v 0 T c T a u u w A M MD m m lm L\ 0 m P\ r L D C S Q p b 0 w 9 w m w w w (AFTER PAOKAG/NG) INVENTOR.AR THUR 6L ICK ATTORNEY Patented A ril 24, 1973 3,728,839

5 Sheets-Sheet 5 INVENTOR. war/1w? GL/CK ATTORNEY STORAGE STABLESURGICALLY ABSORBABLE POLYGLYCOLIC ACID PRODUCTS CROSS-REFERENCES Thisis a Continuation-in-Part of copending applica- 5 tion Ser. No. 788,501filed Jan. 2, 1969, and abandoned in favor hereof.

BACKGROUND OF THE INVENTION At the present time, virtually allabsorbable sutures used in animal and human surgery are prepared frommammalian intestines, such sutures being commonly called catgut sutures.U. S. Pat. No. 3,297,033 describes an absorbable surgical suture madefrom polyglycolic acid. The disclosure therein is incorported byreference. This patent in column 3, lines to 53 disclose othercomponents which may be present in the suture. As set forth therein,polyglycolic acid is also properly named as poly(hydroxyacetic acid) orpolyhydroxyacetic ester.

Polyglycolic stures exhibit great uniformity of com- Q position, ascompared with catgut. They have excellent package strength, i.e.straight pull and knot pull, and desirable in-vivo strength retention.

It has now been found that the desirable package properties and in-vivoproperties of polyglycolic acid surgical elements such as suturesdeteriorate when exposed to moisture. Surprising, the exposure of drypolyglycolic acid sutures to small amounts of moisture for very shortperiods of time is sufficient to cause serious deterioration in thepackage and in-vivo strength of the sutures on long term standing.

If the polyglycolic acid suture for instance is again dried beforepackaging, the storage stability is regained. For instance, polyglycolicacid filaments may be braided at ambient temperature and humidity, in aNew England climate, and if the finished braid is dried to remove allabsorbed moisture, the dried braid is storage stable. For processuniformity and operator comfort, an air conditioned enviomment ispreferred.

Although the reason for the aformentioned affect of j 0 O H II Thelinear dim e r in turn ca'ii'eci'iv'iih thepolymer to break up the highmolecular weight polymer into lower molecular weight chains therebydegrading the polymer and causing a reduction in strength. It is alsopossible that glycolide or the linear dimer of glycolic acid are formedin the polymer as a result of thermal degradation of the polymer whichcan occur during processing such as, for example, in a high temperatureextrusion step. 65

The exact mechanism of hydrolytic attack is somewhat speculative, andnot critical to an explanation or understanding of the presentinvention. One explanation of the hydrolytic attack is that two glycolicacid units can twist to cause a carbonyl carbon to be stericallyapproached by the second nearest oxygen in the backbone of the polymerand incipiently form a six membered ring. This anchiomeric attackweakens that carbonyl-oxygen bond, contributing towards hydrolysis ofthe bond,which thus breaks the polymer chain. [Seez Mechanism andStructure in Organic Chemistry, Edwin S. Gould,I-Iolt, Rinehart andWinston, N.Y., 1959, page 562 and reference therein to Winstein,Lindegren, Marshall and lngraham, J. Am. Chem. Soc. 75, 147 (1953)].

Glycolic acid links in any polymeric chain, particularl y those havingincipient six memberedrings, contribute towards hydrolysis, andfragmentation of the polymer chain into links small enough to be handledby tissue chemistry. The fragmentation is hydrolytic, and does notrequire an enzyme system. The degradation of catgut requires an enzymesystem.

In commercial use, a suture may not be used for months or sometimesyears, after it is packaged. In the meantime, the suture package may bestored under a variety of environmental conditions. Most of thesestorage environments expose the package to some moisture. It ismandatory that such sutures be packaged in a material which will preventpermeation of water vapor from the environment surrounding the packagethrough the package and into contact with the suture contained therein.On the other hand, a package material which prevents the entry of watervapor will ordinarily also prevent the exit of water vapor; therefore,any water vapor which is present within the package when it is sealedwill remain in the package in intimate contact with the suture.Applicant has further discovered that the exposure of a dry suture tomoisture for even extremely brief times (i.e., 20 minutes or less) priorto packaging the suture can have deleterious effects upon the suturewhen it is packaged in a water impermeable package, especially if thepackage should happen to be stored at elevated temperatures.

While primarily for sutures, other polyglycolic acid prosthetic devicesneed to be stored from time of manufacture until time of use.

- As disclosed in said US. Pat. No. 3',297,033,'the polyglycolic acidmay be formed as tubes or sheets for surgical repair and may also bespun as thin filaments and woven or felted to form absorbable sponges orabsorbable gauze, or used in conjuction with other compressivestructures as prosthetic devices within the body of a human or animalwhere it is desirable that the structure have short-term strength, butbe absorbable. The useful embodiments include tubes, including branchedtubes or Tees, for artery, vein or intestinal repair, nerve splicing,tendon splicing, sheets for tying up and supporting damaged kidney,liver and other intestinal organs, protecting damaged surface areas suchas abrasions, particularly major abrasions, or areas where the skin andunderlying tissues are damaged or surgically removed.

In more detail, the medical uses of polyglycolic acid include, but arenot necessarily limited to:

1. Solid Products, molded or machined a. Orthopedic pins, clamps, screwsand plates b. Clips (e.g., for vena cava) c. Staples d. Hooks, buttonsand snaps e. Bone substituted (e.g., mandible prosthesis) f. Needles g.Non-permanent intrauterine devices (anti-spermocide h. Temporarydraining or testing tubes or capillaries 1. Surgical instruments j.Vascular implants or supports k. Vertebral discs I. Extracorporealtubing for kidney and heart-lung machines 2. Fibrillar Products, knittedor woven, including velours a. Burn dressings b. Hernia patches 0.Absorbent paper or swabs d. Medicated dressings e. Facial substitutes f.Gauze, fabric, sheet, felt or sponge for liver hemostasis g. Gauzebandages h. Dental packs 3. Miscellaneous a. Flake or powder for burnsor abrasions b. Foam as absorbable prosthesis c. Substituted for wire infixations d. Film spray for prosthetic devices In Combination with otherComponents 1. Solid Products, molded or machined a. Slowly digestibleion-exchange resin b. Slowly digestible drug release device (pill,pellet) 0. Reinforced bone pins, needles, etc. 7 2. F ibrillar Productsa. Arterial graft or substitutes b. Bandages for skin surfaces 0. Burndressings (in combination with other polymeric films.)

The synthetic character and hence predictable formability andconsistency in characteristics obtainable from a controlled process arehighly desirable.

The most convenient method of sterilizing polyglycolic acid prosthesesis by heat under such conditions that any microorganisms or deleteriousmaterials are rendeted inactive. A second common method is to sterilizeusing a gaseous sterilizing agent such as ethylene oxide. Other methodsof sterilizing include radiation by X-rays, gamma rays, neutrons,electrons, etc., or high intensity ultrasonic vibrational energy orcombinations of these methods. The present materials have such physicalcharacteristics that they may be sterilized by any of these methods.

Strippable packages for sutures are described in U. S. Pat. Nos.3,043,067, Rynkiewicz and Ayres, Suture Package; 2,917,878, Carnariusand Kaufman, Method of Sterile Packing and 2,949,181, Suture Package andProcess of Making Same. 2,734,649, Callahan and Rumpf, MoistureproofVial Closure, shows an appreciation of the type of protection requiredfor moisture sensitive materials.

It is an object of this invention to provide a package for polyglycolicacid products which insures acceptable retention of package and in-vivostrength for prolonged periods of time even under the most undesirableconditions of temperature and humidity. It is another acceptableretention of package and in-vivo strength for object of this inventionto provide a method of preparing such a package.

SUMMARY OF THE INVENTION The present invention is predicated upon thesurprising and unexpected discovery that polyglycolic acid is extremelysensitive to hydrolytic attack, and that while for a period of weeks tomonths, depending on the temperature, may retain a high proportion ofits strength, in the presence of as much as 0.5 percent water, basedupon the weight of the polyglycolic acid; for a preferred storage life,the water or moisture content should be as low as 0.05 percent or less.With the small quantities of polyglycolic acid in a suture package, thetotal quantity of water is best described as bone dry. Exotic analyticaltechniques are required to detect and measure the water content.

This invention relates to a storage stable package for an absorbablesterile synthetic surgical element of a polymer subject to hydrolyticdegradation to non-toxic, tissue-compatible absorbable components, suchas a polyglycolic acid suture. More particularly the invention relatesto a package which comprises an air tight sealed container fabricatedfrom a material which is substantially impervious to water vapor, thecontainer having therein A surgical element such as a polyglycolic acidsuture which is substantially free from water, i.e. bone dry. Thegaseous contents of the container are, prior to sealing the container,either evacuated to yield a vacuum packaged suture or replaced with adry gas which is non-reactive with polyglycolic acid and which issubstantially free from water. A particularly suitable containermaterial is aluminum foil.

A varietyof different packaging materials was evaluated in an attempt tofind a storage stable package for polyglycolic acid sutures. Forexample, when the suture was packaged in Saran (a vinylchloride-vinylidene chloride copolymer) the suture had totallydisintegrated after only 42 days storage at 100F. and 100 percentrelative humidity. A similar result was observed with Scotch Pak film.Scotch Pak is a laminate of polyethylene and the polymeric ester ofethylene glycol and terephthalic acid. Other package materials alsofailed to protect the suture from similar adverse affects. 1

Prior to sealing the suture within the package of this invention, it isessential that the suture bebone dry. The suture can be rendered bonedry by heating for a sufficient period of time to remove the watertherefrom. However it must benoted that once this water is removed, thesuture cannot be allowed to contact an environment containing moisturefor even a very brief period of time, since even such a brief contactcan cause severe deterioration of suture package and in-vivo strengthafter the suture is sealed in a water impervious container and storedfor a prolonged period of time. It therefore becomes necessary when aprocessing gap between when the suture is dried and when it is packagedis anticipated to provide for interim storage in a dry area where thepossibility of contact with moisture is eliminated.

This invention also relates to a method for preparing a storage stablepackage containing therein a sterile polyglycolic acid suture. Such apackage is prepared by inserting the suture into a container which issubstantially impervious to water vapor, sterilizing the suture andcontainer, removing substantially all of the water .from the sterilizedsuture, and then maintaining the ment until the container is to besealed. Prior to sealing the container, the gaseous contents thereof areeither evacuated or replaced with a gas which is non-reactive withpolyglycolic acid and which is substantially free from moisture.

This invention also relates to a method for sterilizing an absorbablepolyglycolic acid with ethylene oxide vapor without adverse effect uponthe package or invivo strength of the suture. In accordance with thisprocess, a non-sterile polyglycolic acid suture is contacted with a gashaving as its active component ethylene oxide. The gas is maintained ata temperature of from about 70 to 90 F. The moisture content of the gasis the ambient moisture content and no additional water is added to thegas to establish any required relativev hmidity therein. When anon-sterile polyglycolic acid suture is contacted with the gas describedabove, sterility of the suture can be achieved with a contact time ofabout 4 hours or more. Suitable sterilization is achieved when thepressure of the sterilizing gas is maintained at about 5 to 30 lbs.psig.

Previous gaseous ethylene oxide sterilization procedures have called fora sterilizing gas maintained at a relatively high pressure (25 psig) andhigh temperature (l130 F Ordinarily, a prescribed relative humidity(i.e. 50 percent) is achieved by adding to the gas that amount of waterwhich is required to establish the desired relative humidity at thetemperature of sterilization. Contact times of 20 hours or more areordinarily used. In view of the aforementioned adverse effect of water,and especially of the effect of water coupled with high temperatures,upon polyglycolic acid, it becomes apparent that sterilizingpolyglycolic acid sutures by such extreme conditions of pressure,temperature, relative humidity as previously used for prolonged periodsof time would be most undesirable. It is known that when polyglycolicacid is contacted with water, and particularly at high temperatures,that degradation of the polymer will occur quite rapidly. Thesterilization process of this invention permits polyglycolic acidsutures to be sterilized at significantly lower temperatures andpressures and shorter time cycles. Additionally, since no moisture isdeliberately added to the sterilized gas and since the compounds of thesterilized gas are anhydrous, the amount of moisture present in thesterilized chamber is significantly less than would be available usingprior ethylene oxide sterilization techniques. Applicant has found thatpolyglycolic acid sutures can be sterilized using the process of thisinvention without adverse effects upon the package or in-vivo propertiesof the suture.

BRIEF DESCRIPTION OF THE DRAWING FIG. 1 is a frontal view of a preferredembodiment of the suture package of this invention.

FIG. 2 is a sectional view taken along the line 2-2 of FIG. 1 and servesto illustrate the laminate structure of a preferred water impermeablecontainer for the polyglycolic suture.

FIG. 3 is a schematic flow sheet depicting a process for preparing thestorage stable polyglycolic acid suture package of this invention.

FIG. 4a shows the effect of the interim conditions which exist betweendrying the suture and packaging the suture in the package of thisinvention upon package straight pull of the suture after storage at FIG.4b shows the effect of the interim conditions which exist between dryingthe suture and packaging the suture in the package of this inventionupon 15 day in-vivo straight pull after storage at 132F.

FIG. 5a compares the storage capabilities of the package of thisinvention with those of an acceptable catgut suture package understorage conditions of l00 F. and percent relative humidity.

FIG. 5b compares the storage capabilities of the package of thisinvention with those of an acceptable catgut suture package understorage condition of 132F. and 10 percent relative humidity.

FIG. 6 shows a suture on a reel label in a single strippable envelope.

. FIG. 7 shows several separate reel labels packaged in a singlestrippable envelope.

FIG. 8 shows several moistureproof envelopes packaged in an outersterile strippable envelope.

DESCRIPTION OF THE PREFERRED EMBODIMENTS FIGS. 1 and 2 present apreferred embodiement of the package of this invention. Referring tothese figures, the package comprises sealed envelope 1 1 containingtherein sterile needled polyglycolic acid suture braid 12 wrapped aroundpaper mounting 13. The package is sealed by peripheral heat seal 14. Thematerial from which envelope 11 is fabricated is a four layered waterimpervious laminate as best seen by reference to FIG. 2. The laminatecomprises a first layer 15 of heat sealable polyethylene, a second layer16 of aluminum foil, a third layer 17 of polyethylene and a fourth layer18 of printable paper. Envelope 11 is conveniently formed by placing twopieces of the aforementioned laminate on top of each other with heatsealable polyethylene layers 15 contacting each other. Three of the fouredges are then sealed together using a standard heated die to form anenvelope into which mounted suture 12 is inserted. After evacuating thecontents of the envelope or replacing them with an anhydrous inert gas,the fourth edge of the envelope is 5 Aluminum foil layer 16 should havea thickness of at least about 0.35 mils in order to insure suitablewater barrier properties with prefered thicknesses of about 0.35 to 1.5mils and a highly preferred thickness of about 0.5 mils.

Polyethylene layer 17 preferably has a thickness of about 0.5 mils. Itsfunction is to serve as an adhesive vehicle for joining togetheraluminum layer 16 and paper layer 18. Of course, any other suitableadhesive would be operable.

Paper layer 18 is preferably 25 lb. super-calendered Bleached PouchPaper (Virgin Sulphate Pulp) having a thickness of about l.l mils i 20percent. The function of paper layer 18 is to permit direct printing oflabels and such on the external surface of the package and hence anyprintable paper would be suitable.

A particularly suitable laminate of polyethylene-aluminumfoil-polyethylene-paper is available from the Riegal Paper Corp., NewYork, N. Y., under the trade designation of Pouchpak.

A convenient method for preparing the package of this invention is shownschematically in FIG. 3. Referring to FIG. 3, surgical needle 19 isaffixed to braided polyglycolic acid suture 20 to produce needledpolyglycolic acid suture braid 12. Braid 12 is then wrapped aroundsuture mounting 1 3. The mounted suture is placed in envelope 11, saidenvelope being prepared as described above.

Envelope 11 containing mounted suture 12 is then placed within a sealedcontainer which is permeable to sterilizing gas but not to bacteria.This container is then placed in a suitable ethylene oxide sterilizingoven. The oven is evacuated after which a mixture of 12 percent byvolume ethylene oxide and 88 percent volume dichlorodifluoromethane(Freon 12) is admitted to the oven. The oven pressure is raised to about10 psig by admitting more of the gas mixture. The temperature of the gasmixture is maintained at 70-90F. The ethylene oxide-Freon mixture isnon-flammable and explosion proof and is safe in all proportions whenmixed with air. The Freon is essentially a diluent and, of course, othersuitable. diluents such as carbon dioxide are also quite suitable. Theimportant aspect about the sterilization process is that thepolyglycolic acid suture can, surprisingly, be sterilized in arelatively dry environment at low temperatures, moderate pressures, andwith very brief sterilization time cycles.

After the suture has been in contact with the sterilizing mixture for atleast 4 hours and preferably 8 hours, the sealed container containingsuture 12 is removed from the ethylene oxide oven and placed in a dryingoven whereupon it is heated'at 180 to 188F. for one hour under a 26 inchvacuum. Sterility of the suture is maintained during this drying stepsince bacteria cannot permeate the container surrounding suture 12. Thecontainer having suture 12 therein is then stored in a dry area 21, i.e.an environment substantially free from moisture, unitl the final sealingof envelope 11. At this point the bacteria proof container containingenvelope 11 and suture 12 isremoved from the dry area 21 and transferredinto sterile area 22 whereupon envelope 1 1 containing suture 12 isremoved from its bacteria-proof container. The gaseous contents ofenvelope 11 are evacuated in sterile area 22 and envelope 12 is heatsealed to produce an air-tight vacuum packaged polygly-colic acidsuture. Alternatively in sterile area 22, the gaseous contents ofenvelope 11 can be replaced by an anhydrous gas which is inert towardspolyglycolic acid such as nitrogen, argon, xenon, helium, hydrogen,carbon dioxide, air, or the like after which envelope 11 is heat sealedto produce a nonvacuum packaged polyglycolic acid suture. Sealedenvelope 11 is then removed from sterile area 22 and inserted intofolded plastic sheet 23. Sheet 23 is heat sealed around envelope 11 bymeans of cathedral seal 24 to form outer strippable envelope 25containing therein sealed, suture containing, inner envelope 11. avariety of materials is suitable for use as outer strippable envelope25. For example various plastic, paper, and metallic foil materials canbe used for this purpose. A particularly suitable material for use asouter envelope 25 is described in U. S. Pat. No. 2,949,181 said patentherein incorporated by reference. The dual envelope suture package isthen placed in an ethylene oxide oven in order to sterilize the outersurfaces of envelope 11, the inner surface of envelope 25 and the voidvolume defined by said surfaces. The ethylene oxide vapor permeatesouter envelope 25 to achieve this sterilization. The mechanics of thissterilization step are well known and are outlined in greater detail inU. S. Pat. No. 2,917,878, said patents herein incorporated by reference.When sterilization is complete a storage stable polyglycolic acid suturepackage is provided which is entirely sterile except for the outersurface of envelope 25. Such package is particularly suitable forserving a sterile suture to a surgeon for use.

in reference to the above process, it is apparent that the sequence andnature of the process steps can be changed somewhat without effectingthe nature of the finished packaged product. For example, suture 12 andenvelope 1] may be separately sterilized and then as sembled in sterilearea 22. Alternatively, suture 12 contained in envelope 11 can be vacuumdried prior to sterilization except that, in that event, a subsequentdrying step would be required if any moisture was picked up by suture inthe sterilization process. Also, suture 12 can be dried prior toinserting it into envelope 11. Of course, a variety of sterilizationtechniques can be used such as heat sterilization, X- rays, beta orgamma radiation and such. However, the preferred method of sterilizationis by gaseous ethylene oxide. Such variations in the sequence and natureof the process steps are apparent to those skilled in the art and aredeemed to fall within the scope of the claims appended hereto.

The polyglycolic acid suture itself may be in any form whatsoever suchas a multifilament braid or a monofilament. It may further be needled,dyed, coated, or otherwise treated in accordance with standard suturetechniques.

Data are presented in Table l which indicate the effect of variousstorage conditions upon the package and in-vivo strength of polyglycolicacid sutures stored in the package of this invention.

TABLE I [Eficct of various storage conditions upon strength retention ofpackaged polyglycolic acid sutures] In-vivo properties 7 After 15 daysAfter 7 days Package properties implantation implantation Percent ofPercent of Percent of original original original Months Suture Straightstrength Straight strength Straight strength smmgo condition t r d sizepull (p.s.i.)- retained pull (p.s.i.) retained pull (p.s.i.) retained 03-0 89, 700 60, 200 28, 300 76 1 R31 3 3-0 88,600 09 64, 900 108 19 20058 l a 3-0 84,500 as 64,900 10s 88 TABLE I- (ontinu In-vivo propertiesAfter 7 days After 15 days Package properties implantation implantationPercent of Percent 01 Percent 1 original original original Months SutureStraight strength Straight strength Straight strength Storage conditionstored slze pull (p.S-1-) retained D1111 (D- retained pull (p.s.l.)retained 00 F., Ambient R.H a 3-0 93,000 104 50,950 as 13, 500 48 6 3-086; 10 96 62, 400 104 19, 500 69 warehousu 3 3-0 03, 600 104 64, 900 10817, 500 62 6 3-0 85, 300 95 68, 200 113 22, 900 81 F, 50% RH 3 1-0 70,400 90 52, 700 107 11,000 82 6 1-0 71, 300 100 51, 200 104 13,100 98 96F., Ambient RH a 1-0 60, s00 08 ,700 107 11,100 as 6 1-0 69, 200 97 52,100 106 9, 900 74 a 1-0 70, s00 08 52,100 100 11, 000 so 6 1-0 68, 800D7 53, 300 108 12, 500 93 13 1 1-0 05,200 01 42, 500 as 5,100 as 1. 41-0 61, 900 87 24, 500 50 870 6 Values are presented as the percent ofthe original strength retained. In reference to package properties, thisterminology means that on day zero of the storage period, the packagestrength of a control (packaged) suture was measured. As storage timeprogressed, package strength (i.e., knot pull and straight pull) wasmeasured at prescribed intervals and compared to the value of thecontrol package strength on day zero to give a percent of strengthretained. In reference to in-vivo strength, this terminology means thata control suture (no storage time) was implanted on day zero of thestorage period in a rabbit for periods of 7 or days after which therabbit was sacrificed and the suture removed. The tensile strength ofthe removed suture was then measured and used as a standard control. Asstorage progressed, sutures at prescribed storage intervals wereimplanted in rabbits as described above and their strength measuredafter 7 or 15 days. This strength was then compared to the strengthobserved with the control suture from day zero to give a percent ofstrength retained."

The data of Table I show the effect of various storage conditions uponthe package and in-vivo straight pull of a size 3-0 and 1-0 suture. Thestrength retention both in the case of package and in-vivo properties isgenerally satisfactory over all the conditions studied except at themoisture existing in either a high or low moisture environmentsurrounding the package from contacting the suture therein. However, asstorage temperatures are raised, rapid deterioration of the suturestrength, and in particular the in-vivo strength of the suture, occursdespite the ability of' the package to prevent the entry of moistureinto the contents of the package.

Data are presented in Table II which indicate why such rapiddeterioration of suture properties occurs after storage at 132F. Certainof these data are presented in FIG. 4a (package straight pull) and F16.4b 15 day in-vivo straight pull) and clearly indicate the importance ofkeeping the suture dry up to the point of packaging it in the package ofthis invention if suture elevated temperatures such as 132F.

TABLE 11 [Eilcct oi pro-packaging environment upon strength retention ofpackaged polyglycolic acid sutures ai'tcr storage under a variety ofconditions] Package properties In'vivo properties after 15 dayimplantation Percent of Percent of Percent of Straight original Knotoriginal Straight original Weeks Condition of suture prior Suture pullstrength pull strength pull strength Storage conditions stored topackaging size (p.s.i.) retained (p.s.i.) retained (p.s.i.) retainedF.,100% R.H Heated at 188 F.1or one gjg 33 838 38g hour under vacuum andthen exposed for 24 hours 0 to an environment h 1 711600 200 500 1 3 3-054 400 76 41 400 0 0 132 F., 10% R.lI 50% relative humidity.

TABLE 11' (nlinued [Eflect oi pre-packaging environment upon strengthretention of packaged polyglycolic acid sutures after storage under avariety of conditions] Package properties In-vivo properties after 15day implantation Percent of Percent of Percent of Straight original Knotoriginal Straight original Weeks Condition oi suture prior Suture pullstrength pull strength pull strength Storage conditions stored topackaging size (p.s.i.) retained (p.s.i.) retained (p.s.i.) retained 03-0 71,600 48,200 0%. 7,500 100 F., 100% R.H Heated at 188 F. for one 33388 @1600 5 000 6 i g f 3-0 66, 700 93 43, 400 no 4, 100 55 o P a 3-0 71600 48 200 7 500 1 1 containing an environment GO'OOO 84 92 3 132 F.,10% R.H 3 having -30% R.H.

6 3-0 0 3-0 1 O -0 100 1* 100% R.1I 3 Heated at 188 F. for one 34)65'500 m 44 800 8 000 107 e under vacuum and 3-0 651600 91 45, 600 10,900 145 0 e immediately p ace 71, 600 48 200 7' 500 F H 1 akdesscam 3066, 600 93 4a, s00 95 2, 700 30 132 10% a age 3-0 es, s00 91 44, s00 035,800 78 6 30 65, 600 91 45, 600 95 4,800 64 I Suture not tested due tounsatisfactory strength values after only one week storage. b Suturedisintegrated and could not be tested.

The data of Table ll detaila study of the effect of the seen from FIGS.4a and 4b, after 6 weeks storage at interim conditions to which thesuture is exposed 132F., the package and in-vivo strength retention ofbetween when it is dried and when it is sealed in the the sutures wereat satisfactory levels. Storage for one package of this invention. Inone case, the dried suture week at 132F. and 10 percent relativehumidity is was exposed to an environment maintained at room equivalentto storage for one year at 72F. and ambient temperature but having 50percent relative humidity hmidity. for 24 hours. The envelope containingthe suture was The above results are provided to clearly indicate thethen sealed, packaged in any outer strippable envelope, importance ofpreserving the suture in a dry state once and stored at 132F. and 10percent relative humidity; it has been dried until it is sealed withinits water-imafter only one week storage at these conditions, thesupervious package. in some cases, even very brief expoture had retainedvirtually no in-vivo strength while sure of dried sutures to moistenvironmental conditions simultaneously its packaged strength hadseverely has, surprisingly, produced extremely rapiddeterioradeteriorated. tion of suture strength when the sutures are sub-In another case a dried suture was stored in a consequently packaged andstored, particularly when tainer at room temperature in an environmenthaving storage occurs under conditions of high temperature 20 to 30percent relative humidity. The suture was then which accelerate theundesirable effect upon the packaged as above. The same rapiddeterioration in supolyglycolic acid suture. ture strength which wasnoted with interim storage Table III presents data which compares thestorage under conditions of percent relative humidity was capabilitiesof the package of this invention with those also observed in this case.of a typical package which is in widespread use for cat- In a finalcase, the dried suture was removed from gut sutures under variousstorage conditions. ,The cutthe drying oven and immediately placed in adessicator 45 gut package referred to is that described in U, S. Pat.where it remained until sealed in its package. As can be No. 2,917,878.

. TABLE 111 [Comparison of the storage capabilities of the package oi.this invention with those of a typical package used with catgut sutures]15-day in-vivo Package properties properties Percent of Percent ofSuture Straight original Straight original Days diameter pull strengthpull strength Packaging material Storage conditions stored Suturematerial (mils) (p.s.i.) retained (p.s.i.) retained 0 11. 9 59,700 8,2707 12. 6 57, 000 6, 1 7 4 Scot ch-lak F., 100% R.II 14 Catgut 12.6 57,300 96 8, 600 104 21 1 12. 7 52, 900 89 3, 660 43 42 12. 7 50, 540 84 4,890 59 0 10. 1 78, 700 12, 000 7 10. 2 75, 900 96 9, 700 8l Package ofthis invention ..do 14 Polyglycolic acid 10. 5 68, 200 87 14, 000 117 2110. 2 74, 700 06 6, 360 63 42 10. 2 75, 900 96 7, 600 63 0 11.! 59, 7008, 270 7 l2. 7 50, 500 84 4, 250 51 Scotcl1-Pak 132 F., 10% Eli. 14Catgut 12. 7 50, 900 85 5, 760 iii! 21 l 12. u 51, 300 as 1, cue 24 4212. 9 47, 460 7!) 4, 660 56 0 10. 1 78, 700 12, 000 7 l0 2 75, 000 9610, 700 88 Package of this invention do 14 Polyglycolie acid 10 5 71,700 00 13,200 21 1 l0 4 76, 600 07 8, 000 67 42 10. 4 75, 400 96 6, 94059 The data of Table III are presented in FIGS. a and 5b. Referring tothese Figures, it is noted that at both storage conditions studied (i.e.100F. 100 percent relative humidity and 132F. percent relativehumidity), the storage capabilities of polyglycolic acid sutures withrespect to both package and in-vivo strength were at least equal to thatof catgut sutures and, in fact, appear to be somewhat better.

The data shown in FIGS. 5a and 5b serve to clearly indicate the abilityof the packageof this invention to provide prolonged stable storage ofabsorbable polyglycolic acid surgical sutures.

FIG. 3 shows a single moistureproof package containing a singlepolyglycolic suture being packaged in a single strippable outer envelope25.

As shown in FIG. 8, if surgical procedures consistently require severalsutures of a given size or pattern of sizes and needle types to be usedat about the same time, several sealed moistureproof envelopes 26, 27and 28 containing a suture may be sealed in a sterile strippable outer.envelope 29 for simultaneous transfer to a sterile operating area andrelease.

As shown in FIG. 7 also several individual sterile absorbablepolyglycolic acid sutures, not necessarily the same size, on severalreels, 30, 31, 32 may be packed in a single moistureproof envelope 33for substantially simultaneous serving the several sutures to a surgeon.The packaging of a single suture in a single moistureproof envelope tobe served from a single strippable envelope permits greater flexibilityand adaptability in operating room techniques--but is by no means theonly system of serving sutures to the surgeon.

For instance, three 36 inch lengths of size 2-0 polyglycolic acidbraided sutures, each havung a medium size /2 circle taper point needleand packaged on separate paper mountings 13, or reels, are packaged in asingle sealed moistureproof envelope for surgical repair afterchildbirth. The group of three is often used for the surgical procedure,and canconveniently be served together. A back-up supply of other sizes,and needle configurations is available on short notice from the operatinroom supply as needed.

A group of three 18 inch lengths of unneedled suture braid size 3-0 areconveniently packaged together to be used as Iigatures in surgery. Aplurality of bleed points often requires several tie-offs.

Present operating room techniques are adapted T6 the presentation of asterile inner moistureproof envelope, with release of the suture fromthis sterile inner envelope at time of use.

As shown in FIG. 6 another economical serving technique is for themoistureproof envelope 36 itself to be the sterile barrier, as well asthe moisture barrier, with the reel-label 35 having the individualsutures wound thereon. Types of such reel-labels are shown in U. S. Pat.No. 3,357,550, l-lolmes & Murphy, Combination Reel and Label forSurgical Sutures, Dec. 12, 1967. One or more such reel-labels carryingsutures permits individual sutures to be served from reels when needed,but the single envelope permits smaller packages, and economy ofpackaging materials. Because polyglycolic acid sutures do not require atubing fluid, an inner envelope to hold such fluid is traditional butanachronistic, and can be eliminated, as surgical procedures in theoperating room are adapted to these streamlined packaging concepts.

Whereas this invention is particularly described in reference tosutures, including ligatures, other polyglycolic acid surgical elementssuch as described in Schmitt and Polistina U. S. Pat. No. 3,463,158Polyglycolic Acid Prosthetic Devices, must be packaged in a dryenvironment for long term storage stability, with retention of fullstrength. This patent describes reinforcing elements such as fabrics fortissue reinforcement or arterial splices which consists in part ofpolyglycolic acid and in part of non-absorbable filaments designed forlong term emplacement and retention in tissue elements.

For surgical items in which strength is not significant, dry storage isnot required. For example for a glove powder, to dust surgical gloves,the material is already in powdered form, and if the powder has lowstrength, and is rapidly absorbed, the product is completely acceptable.

Similarly, if a surgical element, such as a heart valve, is to be usedwithin a few days of manufacture, dry storage is not required. Also,storage at low temperatures, as for example in a refrigerator orfreezer, gives longer useful life, and sutures can be stored even if notdry, for a useful period if kept cool.

Usually, dry packaging to give a useful shelf life of at least threeyears to five years at room, shipping, and warehouse temperatures ispreferred, as controlled storage conditions can add to costs.

Also it is desirable that for surgical supplies, all precautions tosupply the highest standard of product under all conditions be used.Hence a product with short term or special storage characteristicsshould not be used where modern packaging techniques permit greaterstorage stability. I

A unique and unexpected additional advantage of the presentmoistureproof package is that the needles never rust. Carbon steelneedles often rust in tubing fluid, and additives to prevent rust aresometimes used. Here the package is moisture free, rusting on storage isno longer a problem.

An additional advantage pf vacuum packaging in foil is that the outlineof the .-suture and needle show. through the foil laminate. If the foillaminate as supplied has a pinhole in it, the loss of vacuum changes theshape of the package permitting visual inspection.

bther hermetic package scanbe such as sealed glass tubes, sealed tincans, and the like, but such packages are more expensive and lessconvenient than a foil laminate package.

The determination of the moisture content of polyglycolic acid suturesin their envelopes is quite exotic. Certain samples were run in which0.2 gram of a sample was sealed in a moistureproof envelope of the typeherein described and the quantities of moisture were determined.

grams of water on a digital readout. This device uses an electrolyticcell with a phosphorous containing electrolyte to absorb water andmeasures the amount of electricity required to electrolyze the absorbedwater. Dry nitrogen is swept over a sample heated to 125C., which takesup the water with the water being absorbed from the nitrogen in theelectroytic cell, which is then electrolyzed. With a suitable conversionfactor this gives direct reading of the quantity of water.

Inasmuch as the polyglycolic acid itself as well as the paper label areorganic, high temperatures will deocmpose the materials to yield watereven though the water is not present as such at lower temperatures.

Results obtained appears internally consistent, and were consistent withthose found by radio-tracer techniques in which the polyglycolic acidwas exposed to tritiated water, for various lengths of time, and thewater content computed from scintillation count of tritium decay.

The difficulty with accurate analysis can be illustrated by results in atest in which 0.2 gram of polyglycolic acid suture braid was transferredfrom the moistureproof envelope to a sample chamber for moistureanalysis. With a dry braid, with the sample ex placed in moisturechambers at 72F. containing the relative humidity indicated in thetable. These relative humidities were chosen to use convenient saltmixtures which maintain the indicated relative humidity. The envelopeswere permitted to equilibrate for 72 hours, protected by the fiber glasscloth sleeve to keep the packages sterile, after which under sterileconditions, the fiber glass cages were opened and the envelopes sealed.The sealed foiled envelopes with their moisture equilibrated contentswere then packed in an outer strippable polyester-polytheylene laminatepackage which was sterilized through the laminate for 18 hours at 125C.at 26 pounds gauge pressure after which the test packages were eitherused for immediate tests, or stored at 56C. with ambient relativehumidity for l, 3 and 6 weeks as shown in the table. The relativehumidity of the ambient conditions is essentially immaterial inasmuch asmoisture does not pass into or pass out of the sealed foil envelope andaccordingly it is only the temperature which is controlling.

Table IV following shows the moisture of the test chamber in which eachset of braid was dried and the approximate parts per million of water inthe atmosphere at 72F.

' ii-anew Controlled air conditions for 72 hrs. during packaging Percentmoisture in package on braid wt.

15 day in-vivo strength in pounds Package strength-knot pull in straightpull after 56 C. storage Percent RH Parts per Size of pounds after 56 0.storage forform- Sample at. 73 F. at million H2O braid in By CEC, Bytracer,

number (23 C.) 73 F. (23 C.) mils percent percent Initial 1 wk. 3 wks. 6wks. Initial 1 wk. 3 wks. 6 wks.

A 40 6, 900 13. 1 0.53 0.60 (3. 4 2. 7 0 0 .23 0 NT NT B 21 600 13. 1 0.25 0. 19 0. 4 6. 2 4. 7 2. 8 90 8 O 0 C 1O 1, 700 13. 0 0. 16 0. 14 b. 86. 95 6. 5 5. 7 1. 5 3. 0 8 0 D 3 500 12. 8 0. 05 0. 02 7.0 6.9 7. 0 6.5 2. 7 3.3 3. 8 2. 5 E 0. 15 13. 0 0. O2 0. 0012 6. 9 6.8 7. 1 6. J 2. 03. 2 3. 5 3. 0

posed for 5 seconds during the transfer to ambient room conditions of 48percent relative humidity and 70F temperature, the braid absorbed 0.037percent moisture. With a 15 second transfer, the braid ab sorbed 0.076percent moisture. With an exposure of minutes, the moisture rose to 0.39percent. Because of the almost universal occurence of moisture, and itsinnocuous presence .under so many conditions, conditions under which itseffect is deleterious are difficult to ascertain, and difficult tomeasure. Chemistry in a moisture free environment is indeed a rare andexotic phase of science.

A series of tests were run to determine how much moisture is absorbed bythe suture braid from the ambient atmosphere, and the effect of moistureon the sutures. A group of sutures were prepared using a size 2-0 braidwith a blank reel label in each envelope. In each moisture-proof foillaminate envelope were placed two suture lengths of about 7 feet 2inches to give approximately 0.2 grams of braid in each suture length,with two such lengths in each envelope. The sutures were cut, wound,tied in bundles and weighed. A group of envelopes containing sutureswere placed in a fiber glass cloth sleeve, as a bacteria shield andsterilized with a 12 percent ethylene oxide, 88 percent Freon l2 mixturefor 10 hours at 20 pounds gauge and ambient temperature. Aftersterilization, the sutures were vacuum dried for 2 hours at atemperature of about 80C. and less than 1 millimeter mercury totalpressure. Immediately after vacuum drying, the envelopes were whcih theinterior of package was too moist, either the pull strength turned outto be essentially 0, or in some marked NT the suture had degraded so farthat no test could be conducted because the suture was too weak to beemplanted in the test animal.

The above test shows that a useful degree of strength for short termstorage can be obtained with as much as 0.5 percent moisture in theenvelope butfor long term storage stability, it is preferred that themoisture content be not greater than 0.05 percent. An even lower contentof 0.02 percent of moisture based on the weight of the braid in theenvelope gives an extra margin of safety for the storage stability ofthe package.

It is to be noted that the paper of the reel label can act as a moisturetrap and will also hold moisture which can aid in degrading thesuture ifthere is a comparatively high moisture content in the envelope. Wherethe moisture in the envelope is below about 0.05 percent, the amount ofmoisture absorbed on the label is acceptably low and does not lead todegradation of the suture. As the loss of strength is a function of thetime The six weeks tests at 56C. is regarded as being equivalent to atleast 3 years storage under ambient conditions which would includewarehouses, shipping conditions and hospital storage and is regarded asprobably equal to at least 5 years storage under such transientconditions.

Because the temperature of the storage can vary considerably, dependingupon whether the suture is stored in a tropical climate such as Bombay,India, or one of the cooler Alaskan regions, the worst case must beconsidered as controlling in order that the suture will stand up underthe worse set of conditions for a desirable length of time, at least 3to 5 years, and will stand up under less demanding storage conditionsfor extended periods.

A moisture content of below about 0.05 percent water by weight of thepolyglycolic acid braid can be considered as essentially bone dry. Thispermits sealing the dried suture containing envelopes at a relativehumidity of about 2.5 percent at 72F., which corresponds to about 450parts per million of water in the air. A preferred operating range isabout 50 parts per million, so that even if complete equlibration is notattained, the sutures are storage stable for at least 5 years.

lclaim: 1. A method for preparing a storage stable sterile package for asterile synthetic surgical element of a polymer subject to hydrolyticdegradation to non-toxic, tissue-compatible absorbable components, saidpolymer having glycolic acid ester linkages, which comprises:

a. inserting a synthetic surgical element of a polymer subject tohydrolytic degradation to non-toxic, tissue-compatible absorbablecomponents, said polymer having glycolic acid ester linkages, in acontainer which is substantially impervious to water vapor,

b. sterilizing said surgical element and container,

c. removing water until not more than 0.5 percent of 7 water by weightof said surgical element remains,

d. maintaining said surgical element in its dry environment and,

e. sealing said container with an air and moisture resistant seal.

2. The method of claim 1 in which the sterile surgical element is apolyglycolic acid suture.

3. The process of claim 1 in which the water content is less than 0.05percent. 7

4. The method of claim 3 in which the sterile surgical element is apolyglycolic acid suture.

5. A method for preparing the storage stable surgical element package ofclaim 3 which comprises additionally flushing substantiallyallof thegaseous contents out of said container and replacing with a gas which isnon-reactive with polyglycolic acid, and

sealing said container with an air-tight seal.

6. The method of claim 3 which comprises evacuating the container beforesealing, to form an evacuated package.

' r 1- TED STATES PATENT orbits QETEFlfiAT @F @QRE'HQN Patent No-3.'728.839 Dated April 2 1975 Invent fls) Arthur m 1' 0k It is certifiedthat error appears in the above-identified patent and that said LettersPatent are hereby eor'rected as shown below:

Column 1 line 21 "stures" should be sutures Column 5, line 46,-"rendeted" should be rendered Column 5, line 67 "ac-" should bedeleted.

Column 5,, line 68 should be deleted.

Column s," line-25, "A" should be said Column '7, line 19, insert byafter "percent".

Column 7, line 28, before "are" 9 add or other members of the Freonfamily and their mixtures Column 7, line 44, "unitl" should be untilColumn '7, line 52 "-polygly-oolio" should be polyglycolio Column 8,1ihev 7, "a" should be A Column 9, Table I, under "Suture size", 5rdnumber from bottom should be l-O instead of "1-5".

Column 12, line 29, "hmidity" should be humidity 0 Column 15, line 56,"havung" should be having Column 16, line 47, "whcih" should be which 4s hed and sealed this 5th day of Febr ary 7 (SEAL) Attest:

EDWARD M.FLETCHER,JR. RENE D TEGTMEYER Attesting Officer ActingCommissioner of Patents I a FORM P0405, "Mm I uscomn-oc 60376P69 9 0.5.QOVIIIIIIM PIIII'IIG OFFICE "i9 0-386-334

2. The method of claim 1 in which the sterile surgical element is apolyglycolic acid suture.
 3. The process of claim 1 in which the watErcontent is less than 0.05 percent.
 4. The method of claim 3 in which thesterile surgical element is a polyglycolic acid suture.
 5. A method forpreparing the storage stable surgical element package of claim 3 whichcomprises additionally flushing substantially all of the gaseouscontents out of said container and replacing with a gas which isnon-reactive with polyglycolic acid, and sealing said container with anair-tight seal.
 6. The method of claim 3 which comprises evacuating thecontainer before sealing, to form an evacuated package.